Objectives of the project are as follows: first to identify sexual dimorphisms and the role of gonadal steroids in the regulation of neural and glial signal transduction, proliferation, and survival; second, to develop an animal model for behavioral effects of gonadal steroid withdrawal and for the differential behavioral effects of acute alterations in gonadal steroid levels. These objectives serve two overall goals: 1) Understanding neuroregulatory mechanisms of gonadal steroids of relevance for affective disorders; and 2) Defining the substrate of differential sensitivity, the process by which the same hormonal stimulus can elicit different responses in different subjects. Findings in the past year include the following: 1) Demonstration that the strain differences that we observed in the response to estradiol in the forced swim test are not accompanied by differences in the concentration of estrogen receptor alpha or beta proteins (on Western blot) in the cortex, hippocampus, or striatum. 2) Different species of estrogen receptor beta fragments were identified in the nucleus compared with the cytoplasm on fractionation. 3) Opposite effects of estradiol were identified in the learned helplessness paradigm, with estradiol improving the performance of the unstressed animals and impairing the performance of the stressed animals. These findings suggest that genetic differences influence the effect of gonadal steroids in the regulation of neuronal excitability in brain regions mediating the stress response and implicated in depression. Thus, they provide clues to both the susceptibility to and the mediation of reproductive steroid-precipitated mood disturbances.